Lipin-1 Phosphatidic Phosphatase Activity Modulates Phosphatidate Levels to Promote Peroxisome Proliferator-activated Receptor γ (PPARγ) Gene Expression during Adipogenesis

• Published in: The Journal of biological chemistry 2012-01, Vol.287 (5), p.3485-3494
• Main Authors: Zhang, Peixiang, Takeuchi, Kazuharu, Csaki, Lauren S., Reue, Karen
• Format: Article
• Language: English
• Subjects: Adipocyte; Adipocytes - cytology; Adipocytes - metabolism; Adipogenesis - physiology; Animals; Cell Differentiation; Cell Differentiation - physiology; Cells, Cultured; Gene Expression Regulation - physiology; Lipid Synthesis; Lipids; Lipodystrophy; MAP Kinase Signaling System - physiology; Mice; Mice, Mutant Strains; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Phosphatidate Phosphatase - genetics; Phosphatidate Phosphatase - metabolism; Phosphatidic Acids - genetics; Phosphatidic Acids - metabolism; Phospholipid; PPAR gamma - genetics; PPAR gamma - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.296681

Adipose tissue plays a key role in metabolic homeostasis. Disruption of the Lpin1 gene encoding lipin-1 causes impaired adipose tissue development and function in rodents. Lipin-1 functions as a phosphatidate phosphatase (PAP) enzyme in the glycerol 3-phosphate pathway for triglyceride storage and as a transcriptional coactivator/corepressor for metabolic nuclear receptors. Previous studies established that lipin-1 is required at an early step in adipocyte differentiation for induction of the adipogenic gene transcription program, including the key regulator peroxisome proliferator-activated receptor γ (PPARγ). Here, we investigate the requirement of lipin-1 PAP versus coactivator function in the establishment of Pparg expression during adipocyte differentiation. We demonstrate that PAP activity supplied by lipin-1, lipin-2, or lipin-3, but not lipin-1 coactivator activity, can rescue Pparg gene expression and lipogenesis during adipogenesis in lipin-1-deficient preadipocytes. In adipose tissue from lipin-1-deficient mice, there is an accumulation of phosphatidate species containing a range of medium chain fatty acids and an activation of the MAPK/extracellular signal-related kinase (ERK) signaling pathway. Phosphatidate inhibits differentiation of cultured adipocytes, and this can be rescued by the expression of lipin-1 PAP activity or by inhibition of ERK signaling. These results emphasize the importance of lipid intermediates as choreographers of gene regulation during adipogenesis, and the results highlight a specific role for lipins as determinants of levels of a phosphatidic acid pool that influences Pparg expression. Background: Lipin-1-deficient cells cannot differentiate into mature adipocytes. Results: Lipin-1 phosphatidic acid phosphatase activity, but not its coactivator activity, is required for induction of the transcription factor peroxisome proliferator-activated receptor γ (PPARγ). Conclusion: Lipin-1 modulation of phosphatidic acid levels is required for early steps in adipogenesis. Significance: The levels of signaling lipids are important in adipogenesis prior to fat storage.